AGE DOI 10.1007/s11357-014-9624-5
MEG spectral analysis in subtypes of mild cognitive impairment M. E. López & P. Cuesta & P. Garcés & P. N. Castellanos & S. Aurtenetxe & R. Bajo & A. Marcos & M. L. Delgado & P. Montejo & J. L. López-Pantoja & F. Maestú & A. Fernandez
Received: 17 May 2013 / Accepted: 23 January 2014 # American Aging Association 2014
Abstract Mild cognitive impairment (MCI) has been described as an intermediate stage between normal aging and dementia. Previous studies characterized the alterations of brain oscillatory activity at this stage, but little is known about the differences between single and multidomain amnestic MCI patients. In order to study
the patterns of oscillatory magnetic activity in amnestic MCI subtypes, a total of 105 subjects underwent an eyes-closed resting-state magnetoencephalographic recording: 36 healthy controls, 33 amnestic single domain MCIs (a-sd-MCI), and 36 amnestic multidomain MCIs (a-md-MCI). Relative power values were calculated and
M. E. López and P. Cuesta contributed equally to this work. M. E. López (*) : P. Cuesta : P. Garcés : P. N. Castellanos : S. Aurtenetxe : R. Bajo : F. Maestú Laboratory of Cognitive and Computational Neuroscience (UCM-UPM), Centre for Biomedical Technology (CTB), Campus de Montegancedo s/n, Pozuelo de Alarcón, 28223 Madrid, Spain e-mail: [email protected] P. Cuesta e-mail: [email protected] P. Garcés e-mail: [email protected] P. N. Castellanos e-mail: [email protected] S. Aurtenetxe e-mail: [email protected] R. Bajo e-mail: [email protected] F. Maestú e-mail: [email protected] M. E. López : P. Cuesta : S. Aurtenetxe : F. Maestú Department of Basic Psychology II, Complutense University of Madrid, Madrid, Spain P. Garcés CEI Campus Moncloa, UCM-UPM, Madrid, Spain
R. Bajo Department of Mathematics, UNIR Universidad Internacional de La Rioja, Logroño, La Rioja, Spain A. Marcos Neurology Department, San Carlos University Hospital, c/Martín Lagos s/n, 28040 Madrid, Spain e-mail: [email protected] M. L. Delgado Seniors Center of the District of Chamartin, Chamartin S/N, 28002 Madrid, Spain e-mail: [email protected] P. Montejo Memory Decline Prevention Center Madrid Salud, Ayuntamiento de Madrid, c/ Montesa, 22, 28006 Madrid, Spain e-mail: [email protected] J. L. López-Pantoja Department of Psychiatry and Laboratory of Neuroendocrinology, San Carlos University Hospital, c/Martín Lagos s/n, 28040 Madrid, Spain e-mail: [email protected] A. Fernandez Department of Psychiatry and Medical Psychology School of Medicine, Complutense University of Madrid, Madrid, Spain e-mail: [email protected]
AGE
compared among groups. Subsequently, relative power values were correlated with neuropsychological tests scores and hippocampal volumes. Both MCI groups showed an increase in relative power in lower frequency bands (delta and theta frequency ranges) and a decrease in power values in higher frequency bands (alpha and beta frequency ranges), as compared with the control group. More importantly, clear differences emerged from the comparison between the two amnestic MCI subtypes. The a-md-MCI group showed a significant power increase within delta and theta ranges and reduced relative power within alpha and beta ranges. Such pattern correlated with the neuropsychological performance, indicating that the a-md-MCI subtype is associated not only with a “slowing” of the spectrum but also with a poorer cognitive status. These results suggest that a-md-MCI patients are characterized by a brain activity profile that is closer to that observed in Alzheimer disease. Therefore, it might be hypothesized that the likelihood of conversion to dementia would be higher within this subtype. Keywords Mild cognitive impairment . Subtypes . MEG . Relative power . Neuropsychological performance
Introduction The definition of mild cognitive impairment (MCI) underwent a notable evolution during the last two decades. In essence, the concept of MCI was coined to define a clinical condition where an objective cognitive decline can be detected, but this decline is still not severe enough to be considered a full-blown dementia. Petersen and the Mayo Clinic group (Petersen et al. 1999) offered one of the first operational definitions of MCI, which was subsequently accepted by a majority of the scientific community. In the first characterization of Petersen et al. (2001), MCI was a predominantly amnestic problem. MCI was also characterized as a “transitional state.” Thus, this clinical condition would be an intermediate state or a “boundary” between normal aging and dementia, since a number of studies demonstrated that patients with a diagnosis of MCI are at higher risk of developing Alzheimer’s disease (AD) when compared with the healthy aged population (Farias et al. 2005; Petersen 2005; Shah et al. 2000). Following up this evolution, two articles represented a key modification of MCI concept (Petersen 2004;
Winblad et al. 2004). The original notion of a predominant amnestic problem was substituted by a new perspective where several clinical subtypes of MCI were described. This new perspective classified patients according to two orthogonal axes. In the first axis, patients with a predominant memory defect are classified as “amnestic MCI” (a-MCI), while those with a predominant impairment in cognitive domains such as language, executive functions, or visuospatial skills are classified as “nonamnestic MCI” (na-MCI). In the second axis, patients are categorized according to the number of affected cognitive domains. Those with only one affected domain (e.g., memory or language) are categorized as “single domain” MCIs (sd-MCI), while those with more than one affected domain (e.g., memory plus language) are categorized as “multidomain” MCIs (md-MCI). The combination of these axes gives rise to the nowadays more broadly utilized classification of MCI subtypes: amnestic single domain MCI (a-sd-MCI), amnestic multidomain MCI (amd-MCI), nonmanestic single domain MCI (nasd-MCI), and nonamnestic multidomain MCI (namd-MCI). This clinical classification is extremely relevant because each subtype is linked to a presumed etiology. According to Petersen’s group, the amnestic subtypes (including single and multidomain) represent a prodromal form of AD, although vascular dementia may be also considered (Petersen 2004). Nonamnestic subtypes might be at higher risk of conversion to Lewy–body or frontotemporal dementias (Petersen 2004; Winblad et al. 2004). Implicitly, this categorization still assumes that MCI is a “predementia” stage, and most patients would convert to some type of dementia if they are followed up for enough time. However, investigations such as the population-based PAQUID study (Larrieu et al. 2002) demonstrated that this implicit assumption was not totally true. On the contrary, MCI emerged as an unstable clinical condition, with some patients progressing to different dementias, some patients remaining clinically stable over time, and notably some patients reverting to a “normal” clinical situation (40 % in the PAQUID study for example). As a consequence of this new scenario, recent proposals of MCI diagnostic criteria (Albert et al. 2011) claim the utilization of a very strict terminology (i.e., “MCI due to AD”), since different etiologies that yield different outcomes (including the reversion to a “normal” condition) might be underlying the observed cognitive deterioration.
AGE
Despite of the new consideration of MCI as an unstable condition, there is still solid evidence supporting the higher risk of conversion to dementia (especially AD) in this group of patients (Bennett et al. 2005; Gauthier et al. 2006; Morris et al. 2001). Therefore, the early detection of MCI is still a critical issue regarding the development of interventions to prevent or delay the process of neurodegeneration (Jelic et al. 2005). In order to attain such goal, it is important to bear in mind that clinical subtypes of MCI are not only associated with different etiologies but also with a more or less rapid conversion to dementia (Brodaty et al. 2012; Tabert et al. 2006). Considering this fact, a great effort has been devoted to investigate biological markers that may characterize the clinical subtypes of MCI. Neurophysiological techniques such as electroencephalography (EEG) or magnetoencephalography (MEG) played a significant role in this line of research. The most stable pattern of EEG activity in MCI patients is defined by an increase in theta accompanied by a decrease of alpha and beta power, which correlates with APOE genotype, and hippocampal volumes (Babiloni et al. 2006b, c, 2009; Grunwald et al. 2002; Prichep et al. 2006). When the progression to AD was investigated, alpha and theta relative power in left temporooccipital derivation correctly classified 85 % of MCI subjects who would suffer dementia (Jelic et al. 2000). Huang et al. (2000) demonstrated that a more anterior localization of theta and alpha activity was the best predictor of future conversion to AD within a MCI sample. Of note, the investigation of differential neurophysiological patterns in MCI subtypes is scarce. This issue was indirectly addressed by Babiloni et al. (2009) within the background of a research on the relationship between hippocampal volumes and alpha rhythms. The authors assessed a potential influence of the clinical subtype (i.e., a-MCI vs. na-MCI) and found no significant differences. In a subsequent study (Babiloni et al. 2010), the issue was explicitly investigated by comparing EEG rhythms in a-MCIs, na-MCIs, and aged subjects with subjective memory complaints. Results showed increased occipital theta and reduced alpha activity in a-MCI, as compared to na-MCI. No distinctions were made in terms a single or multidomain affectation. Considering the scarcity of studies within this field and its potential clinical relevance, we conducted a MEG study where an exhaustive spectral analysis was carried out in a-sd-MCIs, a-md-MCIs, and healthy aged
controls. Recently, a-md-MCI has been associated with increased levels of AD pathology and elevated risk of conversion to AD when compared with a-sd-MCI (Zhang et al. 2012; Brodaty et al. 2012; Wolk et al. 2009). As a consequence, we not only expect the typical pattern of increased theta and reduced alpha in the MCI groups. Furthermore, we hypothesize that a-md-MCI patients will exhibit a spectral pattern more proximate to the typical AD profile, including increased power within the delta and theta frequency ranges, and reduced activity in the high-frequency range as compared with asd-MCIs and healthy controls. Finally, bearing in mind that mesial–temporal atrophy is one of the more important markers within the normal aging-AD spectrum (see, for example, Jack et al. 1999; Martin et al. 2010), hippocampal volumes were calculated in order to assess the relationship between structural and functional information. To the best of our knowledge, this is the first neurophysiological study that combines spectral activity, neuropsychological performance, and hippocampal atrophy information to characterize the two amnesic clinical subtypes of MCI.
Methods Subjects MEG signals were obtained from 105 subjects older than 65 years of age, classified in three groups: 36 healthy controls, 33 a-sd-MCI patients, and 36 a-mdMCI patients. All of them were right-handed (Oldfield 1971) and native Spanish speakers. No significant differences were found in education, gender, or age among groups (see Table 1). MCI patients were recruited from the Geriatrics and Neurology Units of the “Hospital Universitario San Carlos” and the “Memory Decline Prevention Center,” both in Madrid, Spain. Healthy volunteers were recruited from the “Seniors Center of Chamartin District,” Madrid. Diagnostic criteria All participants were screened by means of a variety of standardized diagnostic instruments that included: the Spanish version of the Mini Mental State Examination (MMSE; Lobo et al. 1979), the Global Deterioration Scale (GDS; Reisberg et al. 1982), the Functional assessment questionnaire (FAQ; Pfeffer et al. 1982), the
AGE Table 1 Mean values (±standard deviation) of the demographic and clinical characteristics of a-sd-MCI, a-md-MCI, and controls Control (n=36)
a-sd-MCI (n=33)
a-md-MCI (n=36)
p value
Age (years)
72.36±4.75
74.15±6.07
73.94±3.70
p=0.22
Gender (M/F)
11/25
13/20
13/23
p=0.12
MMSE score
29.14±0.96
27.63±2.47
25.65±2.66
p
MEG spectral analysis in subtypes of mild cognitive impairment M. E. López & P. Cuesta & P. Garcés & P. N. Castellanos & S. Aurtenetxe & R. Bajo & A. Marcos & M. L. Delgado & P. Montejo & J. L. López-Pantoja & F. Maestú & A. Fernandez
Received: 17 May 2013 / Accepted: 23 January 2014 # American Aging Association 2014
Abstract Mild cognitive impairment (MCI) has been described as an intermediate stage between normal aging and dementia. Previous studies characterized the alterations of brain oscillatory activity at this stage, but little is known about the differences between single and multidomain amnestic MCI patients. In order to study
the patterns of oscillatory magnetic activity in amnestic MCI subtypes, a total of 105 subjects underwent an eyes-closed resting-state magnetoencephalographic recording: 36 healthy controls, 33 amnestic single domain MCIs (a-sd-MCI), and 36 amnestic multidomain MCIs (a-md-MCI). Relative power values were calculated and
M. E. López and P. Cuesta contributed equally to this work. M. E. López (*) : P. Cuesta : P. Garcés : P. N. Castellanos : S. Aurtenetxe : R. Bajo : F. Maestú Laboratory of Cognitive and Computational Neuroscience (UCM-UPM), Centre for Biomedical Technology (CTB), Campus de Montegancedo s/n, Pozuelo de Alarcón, 28223 Madrid, Spain e-mail: [email protected] P. Cuesta e-mail: [email protected] P. Garcés e-mail: [email protected] P. N. Castellanos e-mail: [email protected] S. Aurtenetxe e-mail: [email protected] R. Bajo e-mail: [email protected] F. Maestú e-mail: [email protected] M. E. López : P. Cuesta : S. Aurtenetxe : F. Maestú Department of Basic Psychology II, Complutense University of Madrid, Madrid, Spain P. Garcés CEI Campus Moncloa, UCM-UPM, Madrid, Spain
R. Bajo Department of Mathematics, UNIR Universidad Internacional de La Rioja, Logroño, La Rioja, Spain A. Marcos Neurology Department, San Carlos University Hospital, c/Martín Lagos s/n, 28040 Madrid, Spain e-mail: [email protected] M. L. Delgado Seniors Center of the District of Chamartin, Chamartin S/N, 28002 Madrid, Spain e-mail: [email protected] P. Montejo Memory Decline Prevention Center Madrid Salud, Ayuntamiento de Madrid, c/ Montesa, 22, 28006 Madrid, Spain e-mail: [email protected] J. L. López-Pantoja Department of Psychiatry and Laboratory of Neuroendocrinology, San Carlos University Hospital, c/Martín Lagos s/n, 28040 Madrid, Spain e-mail: [email protected] A. Fernandez Department of Psychiatry and Medical Psychology School of Medicine, Complutense University of Madrid, Madrid, Spain e-mail: [email protected]
AGE
compared among groups. Subsequently, relative power values were correlated with neuropsychological tests scores and hippocampal volumes. Both MCI groups showed an increase in relative power in lower frequency bands (delta and theta frequency ranges) and a decrease in power values in higher frequency bands (alpha and beta frequency ranges), as compared with the control group. More importantly, clear differences emerged from the comparison between the two amnestic MCI subtypes. The a-md-MCI group showed a significant power increase within delta and theta ranges and reduced relative power within alpha and beta ranges. Such pattern correlated with the neuropsychological performance, indicating that the a-md-MCI subtype is associated not only with a “slowing” of the spectrum but also with a poorer cognitive status. These results suggest that a-md-MCI patients are characterized by a brain activity profile that is closer to that observed in Alzheimer disease. Therefore, it might be hypothesized that the likelihood of conversion to dementia would be higher within this subtype. Keywords Mild cognitive impairment . Subtypes . MEG . Relative power . Neuropsychological performance
Introduction The definition of mild cognitive impairment (MCI) underwent a notable evolution during the last two decades. In essence, the concept of MCI was coined to define a clinical condition where an objective cognitive decline can be detected, but this decline is still not severe enough to be considered a full-blown dementia. Petersen and the Mayo Clinic group (Petersen et al. 1999) offered one of the first operational definitions of MCI, which was subsequently accepted by a majority of the scientific community. In the first characterization of Petersen et al. (2001), MCI was a predominantly amnestic problem. MCI was also characterized as a “transitional state.” Thus, this clinical condition would be an intermediate state or a “boundary” between normal aging and dementia, since a number of studies demonstrated that patients with a diagnosis of MCI are at higher risk of developing Alzheimer’s disease (AD) when compared with the healthy aged population (Farias et al. 2005; Petersen 2005; Shah et al. 2000). Following up this evolution, two articles represented a key modification of MCI concept (Petersen 2004;
Winblad et al. 2004). The original notion of a predominant amnestic problem was substituted by a new perspective where several clinical subtypes of MCI were described. This new perspective classified patients according to two orthogonal axes. In the first axis, patients with a predominant memory defect are classified as “amnestic MCI” (a-MCI), while those with a predominant impairment in cognitive domains such as language, executive functions, or visuospatial skills are classified as “nonamnestic MCI” (na-MCI). In the second axis, patients are categorized according to the number of affected cognitive domains. Those with only one affected domain (e.g., memory or language) are categorized as “single domain” MCIs (sd-MCI), while those with more than one affected domain (e.g., memory plus language) are categorized as “multidomain” MCIs (md-MCI). The combination of these axes gives rise to the nowadays more broadly utilized classification of MCI subtypes: amnestic single domain MCI (a-sd-MCI), amnestic multidomain MCI (amd-MCI), nonmanestic single domain MCI (nasd-MCI), and nonamnestic multidomain MCI (namd-MCI). This clinical classification is extremely relevant because each subtype is linked to a presumed etiology. According to Petersen’s group, the amnestic subtypes (including single and multidomain) represent a prodromal form of AD, although vascular dementia may be also considered (Petersen 2004). Nonamnestic subtypes might be at higher risk of conversion to Lewy–body or frontotemporal dementias (Petersen 2004; Winblad et al. 2004). Implicitly, this categorization still assumes that MCI is a “predementia” stage, and most patients would convert to some type of dementia if they are followed up for enough time. However, investigations such as the population-based PAQUID study (Larrieu et al. 2002) demonstrated that this implicit assumption was not totally true. On the contrary, MCI emerged as an unstable clinical condition, with some patients progressing to different dementias, some patients remaining clinically stable over time, and notably some patients reverting to a “normal” clinical situation (40 % in the PAQUID study for example). As a consequence of this new scenario, recent proposals of MCI diagnostic criteria (Albert et al. 2011) claim the utilization of a very strict terminology (i.e., “MCI due to AD”), since different etiologies that yield different outcomes (including the reversion to a “normal” condition) might be underlying the observed cognitive deterioration.
AGE
Despite of the new consideration of MCI as an unstable condition, there is still solid evidence supporting the higher risk of conversion to dementia (especially AD) in this group of patients (Bennett et al. 2005; Gauthier et al. 2006; Morris et al. 2001). Therefore, the early detection of MCI is still a critical issue regarding the development of interventions to prevent or delay the process of neurodegeneration (Jelic et al. 2005). In order to attain such goal, it is important to bear in mind that clinical subtypes of MCI are not only associated with different etiologies but also with a more or less rapid conversion to dementia (Brodaty et al. 2012; Tabert et al. 2006). Considering this fact, a great effort has been devoted to investigate biological markers that may characterize the clinical subtypes of MCI. Neurophysiological techniques such as electroencephalography (EEG) or magnetoencephalography (MEG) played a significant role in this line of research. The most stable pattern of EEG activity in MCI patients is defined by an increase in theta accompanied by a decrease of alpha and beta power, which correlates with APOE genotype, and hippocampal volumes (Babiloni et al. 2006b, c, 2009; Grunwald et al. 2002; Prichep et al. 2006). When the progression to AD was investigated, alpha and theta relative power in left temporooccipital derivation correctly classified 85 % of MCI subjects who would suffer dementia (Jelic et al. 2000). Huang et al. (2000) demonstrated that a more anterior localization of theta and alpha activity was the best predictor of future conversion to AD within a MCI sample. Of note, the investigation of differential neurophysiological patterns in MCI subtypes is scarce. This issue was indirectly addressed by Babiloni et al. (2009) within the background of a research on the relationship between hippocampal volumes and alpha rhythms. The authors assessed a potential influence of the clinical subtype (i.e., a-MCI vs. na-MCI) and found no significant differences. In a subsequent study (Babiloni et al. 2010), the issue was explicitly investigated by comparing EEG rhythms in a-MCIs, na-MCIs, and aged subjects with subjective memory complaints. Results showed increased occipital theta and reduced alpha activity in a-MCI, as compared to na-MCI. No distinctions were made in terms a single or multidomain affectation. Considering the scarcity of studies within this field and its potential clinical relevance, we conducted a MEG study where an exhaustive spectral analysis was carried out in a-sd-MCIs, a-md-MCIs, and healthy aged
controls. Recently, a-md-MCI has been associated with increased levels of AD pathology and elevated risk of conversion to AD when compared with a-sd-MCI (Zhang et al. 2012; Brodaty et al. 2012; Wolk et al. 2009). As a consequence, we not only expect the typical pattern of increased theta and reduced alpha in the MCI groups. Furthermore, we hypothesize that a-md-MCI patients will exhibit a spectral pattern more proximate to the typical AD profile, including increased power within the delta and theta frequency ranges, and reduced activity in the high-frequency range as compared with asd-MCIs and healthy controls. Finally, bearing in mind that mesial–temporal atrophy is one of the more important markers within the normal aging-AD spectrum (see, for example, Jack et al. 1999; Martin et al. 2010), hippocampal volumes were calculated in order to assess the relationship between structural and functional information. To the best of our knowledge, this is the first neurophysiological study that combines spectral activity, neuropsychological performance, and hippocampal atrophy information to characterize the two amnesic clinical subtypes of MCI.
Methods Subjects MEG signals were obtained from 105 subjects older than 65 years of age, classified in three groups: 36 healthy controls, 33 a-sd-MCI patients, and 36 a-mdMCI patients. All of them were right-handed (Oldfield 1971) and native Spanish speakers. No significant differences were found in education, gender, or age among groups (see Table 1). MCI patients were recruited from the Geriatrics and Neurology Units of the “Hospital Universitario San Carlos” and the “Memory Decline Prevention Center,” both in Madrid, Spain. Healthy volunteers were recruited from the “Seniors Center of Chamartin District,” Madrid. Diagnostic criteria All participants were screened by means of a variety of standardized diagnostic instruments that included: the Spanish version of the Mini Mental State Examination (MMSE; Lobo et al. 1979), the Global Deterioration Scale (GDS; Reisberg et al. 1982), the Functional assessment questionnaire (FAQ; Pfeffer et al. 1982), the
AGE Table 1 Mean values (±standard deviation) of the demographic and clinical characteristics of a-sd-MCI, a-md-MCI, and controls Control (n=36)
a-sd-MCI (n=33)
a-md-MCI (n=36)
p value
Age (years)
72.36±4.75
74.15±6.07
73.94±3.70
p=0.22
Gender (M/F)
11/25
13/20
13/23
p=0.12
MMSE score
29.14±0.96
27.63±2.47
25.65±2.66
p
